Identification of RO4597014, a Glucokinase Activator Studied in the Clinic for the Treatment of Type 2 Diabetes

被引：13

作者：

Qian, Yimin ^{[1
]}

Corbett, Wendy L. ^{[1
]}

Berthel, Steven J. ^{[1
]}

Choi, Duk Soon ^{[2
]}

Dvorozniak, Mark T. ^{[3
]}

Geng, Wanping ^{[4
]}

Gillespie, Paul ^{[1
]}

Guertin, Kevin R. ^{[1
]}

Haynes, Nancy-Ellen ^{[1
]}

Kester, Robert F. ^{[1
]}

Mennona, Francis A. ^{[1
]}

Moore, David ^{[4
]}

Racha, Jagdish ^{[4
]}

Radinov, Roumen ^{[5
]}

Sarabu, Ramakanth ^{[1
]}

Scott, Nathan R. ^{[1
]}

Grimsby, Joseph ^{[3
]}

Mallalieu, Navita L. ^{[6
]}

机构：

[1] Hoffmann La Roche Inc, Dept Discovery Chem, Nutley, NJ 07110 USA

[2] Hoffmann La Roche Inc, Dept Pharmaceut & Analyt Res, Nutley, NJ 07110 USA

[3] Hoffmann La Roche Inc, Dept Metab & Vasc Dis, Nutley, NJ 07110 USA

[4] Hoffmann La Roche Inc, Dept Drug Metab & Pharmacokinet, Nutley, NJ 07110 USA

[5] Hoffmann La Roche Inc, Dept Proc Res, Nutley, NJ 07110 USA

[6] Hoffmann La Roche Inc, Dept Clin Pharmacol, Nutley, NJ 07110 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 04期

关键词：

Glucokinase activator; type; 2; diabetes; lipophilic ligand efficiency; metabolite; redox cycling; BENZAMIDE DERIVATIVES; DISCOVERY; DESIGN; CANDIDATE; EFFICACY; THERAPY; SAFETY; POTENT;

D O I：

10.1021/ml400027y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

To resolve the metabolite redox cycling associated with our earlier clinical compound 2, we carried out lead optimization of lead molecule 1. Compound 4 showed improved lipophilic ligand efficiency and demonstrated robust glucose lowering in diet-induced obese mice without a liability in predictive preclinical drug safety studies. Thus, it was selected as a clinical candidate and further studied in type 2 diabetic patients. Clinical data suggests no evidence of metabolite cycling, which is consistent with the preclinical profiling of metabolism.

引用

页码：414 / 418

页数：5

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